Is CHD8 p.Ser395Pro (c.1183T>C) pathogenic?

CHD8 p.Ser395Pro (c.1183T>C) is classified Uncertain significance in CHD8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-05). AlphaMissense: likely benign (0.1921); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with CHD8 p.Ser395Pro (c.1183T>C)?

CHD8 p.Ser395Pro (c.1183T>C) is associated with Inborn genetic diseases (ClinVar).

How common is CHD8 p.Ser395Pro (c.1183T>C) in the general population?

CHD8 p.Ser395Pro (c.1183T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CHD8 p.Ser395Pro (c.1183T>C)?

AlphaMissense predicts likely benign (score 0.1921) — an in-silico prediction, not a clinical call.

CHD8 p.Ser395Pro

c.1183T>C · rs2502006297 · VCV2836101

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1921 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1921	likely benign
REVEL	0.315	indeterminate
SaProt	LLR -5.99	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.9	GERP 2.8, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 1,193 bp · p 0.15 · regional, not allelic
Overall
CADD	21.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CHD8
Protein: p.Ser395Pro
Coding: c.1183T>C
MANE Select: NM_001170629
dbSNP: rs2502006297
Type: single nucleotide variant
Location: chr14:21428996 (GRCh38)
Gene constraint: LOEUF 0.154 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 55.17 · 2 PDB

Full CHD8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CHD8 p.Ser395Leu Uncertain significance ★★ ⚠ same residue
CHD8 p.Ser395Ter Likely pathogenic ★ same residue
CHD8 c.3882+1G>A Pathogenic/Likely pathogenic ★★ same condition
CHD8 p.Arg1462Ter Pathogenic ★★ same condition
CHD8 p.Arg1582Ter Pathogenic/Likely pathogenic ★★ same condition
CHD8 p.Arg2217Ter Pathogenic ★★ same condition
CHD8 p.Arg243Ter Pathogenic ★★ same condition
CHD8 c.4921+4C>T Uncertain significance ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/chd8-p-ser395pro (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown